EP2780041A1 - Multimodal contrast and radiopharmaceutical agent for an imaging and a targeted therapy guided by imaging - Google Patents
Multimodal contrast and radiopharmaceutical agent for an imaging and a targeted therapy guided by imagingInfo
- Publication number
- EP2780041A1 EP2780041A1 EP11811123.6A EP11811123A EP2780041A1 EP 2780041 A1 EP2780041 A1 EP 2780041A1 EP 11811123 A EP11811123 A EP 11811123A EP 2780041 A1 EP2780041 A1 EP 2780041A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- nanoprobes
- group
- formula
- imaging
- mmol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
- A61K51/0478—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group complexes from non-cyclic ligands, e.g. EDTA, MAG3
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
- A61K49/1818—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
- A61K49/1821—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles
- A61K49/1824—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/004—Acyclic, carbocyclic or heterocyclic compounds containing elements other than carbon, hydrogen, halogen, oxygen, nitrogen, sulfur, selenium or tellurium
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/10—Organic compounds
- A61K49/12—Macromolecular compounds
- A61K49/124—Macromolecular compounds dendrimers, dendrons, hyperbranched compounds
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T428/00—Stock material or miscellaneous articles
- Y10T428/29—Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
- Y10T428/2982—Particulate matter [e.g., sphere, flake, etc.]
Definitions
- the present invention relates to a multimodal contrast and radiopharmaceutical agent for an imaging and a targeted therapy guided by imaging.
- MRI magnetic resonance imaging
- PET positron emission tomography
- SPECT single photon emission computed tomography
- the dendritic globular shape could improve the coupling stability with the biological effectors as well as the thermodynamic and kinetic stability of the metallic complex.
- dendrimers or dendritic compounds for biomedical applications is a flourishing area of research, mainly because of their precisely defined structure and high tunability, leading to biocompatible, polyfunctionnal and water-soluble systems (S. E. Stiriba, H. Frey and R. Haag, Angew. Chem. Int. Ed , 2002, 41, 1329-1334; M. J. Cloninger, Curr. Opin. Chem. Biol, 2002, 6, 742-748; R. Duncan and L. Izzo, Adv. Drug Delivery Rev. , 2005, 57, 2215-2237; C. C. Lee, J. A. MacKay, J. M. J. Frechet and F. C. Szoka, Nat. Biotechnol , 2005, 23, 1517-1526; O. Rolland, C-O. Turrin, A-M. Caminade, J-P. Majoral, New J. Chem. , 2009, 33, 1809-1824).
- MRI contrast agents as a new class of macromolecular (MRI) contrast agents.
- the efficiency of MRI contrast agents is often expressed in terms of their longitudinal relaxivity (ri/mM _1 .s_i), i.e. their ability to shorten the longitudinal relaxation time of protons of water molecules (Ti/s).
- Rudovsky et al. studied the effect on ri of the ionic interactions between negatively charged Gd(III)-based PAMAM dendrimers and positively-charged poly(aminoacids) (J. Rudovsky, P. Hermann, M. Botta, S. Aime and I. Lukes, Chem. Commun., 2005, 2390). Titration experiments on the second generation dendritic contrast agent with poly(arginine) showed an increase in ri from 20 to 28 mM "1 . s "1 (0.47 T, 20°C). This effect was attributed to a decrease in the mobility of the Gd(III) complex, induced by interactions between the anionic dendrimer and the cationic poly(arginine).
- dendrimers have shown to be suitable synthetic scaffolds for the incorporation of multiple Gd(III) moieties, leading to an improved sensitivity for MRI in terms of x ⁇ . These conclusions are based on measurements at current magnetic fields of 0.5- 1.5 T. However, at high magnetic fields of 10 T, the ri values of dendritic contrast agents are substantially lower, not exceeding the ri values of low molecular weight Gd(III)-based complexes. Dendrimers also improve the protection of the gadolinium and its stability and thus decrease the toxicity risks .
- the dendritic MRI contrast agents are excellent blood pool agents. However, these structures lack the specificity required for molecular MRI (D. Artemov, J. Cell. Biochem., 2003, 90, 518). The development of target-specific MRI contrast agents, directed to defined molecular markers, could dramatically improve the targeting and imaging of a specific disease, due to the accumulation of MRI contrast agent at the region of interest,
- - M is a magnetic cation, in particular chosen among Gd 3+ , Mn 2+ and 99mTc 3+ ,
- - [D] is a dendritic structure having a core comprising at least one group derived from benzyl alcohol or a benzylamine, the benzyl cycle of which is substituted in positions 3, 4, 5 by dendrites composed of polyethyleneglycol pattern,
- - m is an integer being equal to 1 or 2 or 4,
- - Xi is a group increasing the complex lipophily, such as a tert-butyl group (tBu),
- - pi is an integer from 0 to 12
- - X2 is a group increasing the complex specificity for a particular organ, preferably for the brain, such as L-dopamine,
- - p2 is an integer being equal to 0, 1 , 2, or 4,
- - X3 un group having a therapeutic activity preferably for neurodegeneratives diseases such as Alzheimer disease, Parkinson disease and multiple sclerosis,
- - p3 is an integer equal to 0, 1 , 2, or 4,
- - X4 is a CH3 group
- - p4 is an integer from 0 to 12
- - z is an integer equal to 0, 1 , 2, 3 or 4.
- preferred compounds are complexes of the formula defined above wherein dendrites of each structure [D] are functionalized with L- Dopamine but it is well known for a man skilled in the art that dopamine does not cross the blood brain barrier and further the specification discloses a dendrite [D] that is not functionalized with L-Dopamine but with a 3,4 OH phenylglycine.
- example 2 discloses the synthesis of compound of formula III- 1 to III-3 but said synthesis could not be achieved as the compound disclosed before the reaction with a metallic moiety could not lead at all said formulas.
- One of the aims of the present invention is to provide dendritic nanoprobes comprising several identical or different recognition elements of a target cell, in particular a cancer cell displaying important targeting capacities and allowing the vectorization of diagnostic or therapeutic agent through the complexation of very diverse metallic ions, said dendritic nanoprobes being liable to cross the blood brain barrier.
- Another aim of the invention is to provide dendritic nanoprobes as a medicament, suitable especially for detecting and/or treating a cancer cell or tissue or organ.
- Still another aim of the invention is to provide pharmaceutical or diagnostic compositions comprising dendritic nanoprobes.
- the present invention relates to functionalized dendritic nanoprobes of the following formula (I)
- R and R represent independently from each other a chain composed of oligoethyleneglycol patterns, at least one of said oligoethyleneglycol chain being functionalized at its extremity by a group chosen among a biological molecule, a fluorophore, or a biocompatible dye and R 5 represents an hydrogen atom or a chain composed of oligoethyleneglycol patterns, said chain being optionally functionalized at its extremity by a group chosen among a biological molecule, a fluorophore, or a biocompatible dye,
- X represents a group of the following formula (II):
- p is comprised from 3 to 6
- the word "functionalized” means that in the compounds of formula (I) at least one of R4 to R6 groups is functionalized by a biological molecule, a fluorophore or a dye.
- oligoethyleneglycol pattern refers to the following structure:
- n is an integer varying from 1 to 10
- r is an integer varying from 1 to 20,
- R a and R b are independently from each other a linear or branched (Ci-Cio)-alkyl group or a biological molecule, a fluorophore or a dye.
- Alkyl group can be methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and isomers thereof.
- alkyl group is methyl or tert-butyl.
- biological molecule a molecule liable to display a biological function, i.e. any molecule produced by a living organism, such as lipids, phospholipids, glycolipids, sterols, glycerolipids, vitamins, hormones, neurotransmitters, amino-acids, saccharides, nucleotides, antibodies, without being limited to them, or any chemically produced molecule such as a drug or an active principle.
- fluorophore refers to fluorescent molecules such as cyanins, alexa... well known from a man skilled in the art, in particular fluorophore used in FACS method, but without being limited to them.
- dye refers to any natural dye liable to be used as a dye for food, pharmaceutical or cosmetical products, such as those disclosed in M. Perez-Urquiza et al (2001) J. Chrom. 917, 331-336.
- the dye has a blue color to better identify cells or tissues.
- Patent Blue V also called Food Blue 5 or Sulphan Blue, or patent blue Vf having respectively the following formulas, can be used:
- Each dendritic structure, or dendron, for generations higher than 1, comprises a structure of the type dendrons of Frechet such as described in Dendrimers and other dendritic polymers, J. M. J Frechet, D.A. Tomalia, Wiley, New York, 2001 having the following formula (D):
- R a , R b and R c represent independently from each other, an linear or branched alkyl group, a biological molecule, a fluorophore or a dye, n is an integer comprised from 1 to 10 and r is an integer comprised from 1 to 20.
- compounds of formula I could be poly functionalized, i.e. they can bear several different biological molecules and/or different fluorophores and/or different dyes to detect specific cells, in particular cancer cells and in particular in the brain. Said polyfunctionalization leading for example to a specific recognition of cancer cells vis-avis of normal cells.
- Another advantage of the invention is that the specific recognition of a cancer cells may lead to the specific delivery of an active principle to said cancer cell if the compound of formula I bear at least one active principle, such as an anticancer drug.
- compounds of formula (I) are functionalized by one or two or three biological molecules and/or fluorophores and/or dyes for generation 1, by one or two or three or four or five biological molecules and/or fluorophores and/or dyes for generation 2, by one or two or three or four or five or six or seven biological molecules and/or fluorophores and/or dyes for generation 3, and so on.
- a nanoprobes bearing several biological molecules and/or fluorophores and/or dyes, identical or different, is liable to recognize specifically a tumor cell as tumor cell differ from normal cells only by an overexpression of cell markers
- the recognition is specific, it allows treating specifically the tumor cell and not the normal cell and thus to decrease the toxicity of the therapy and/or increasing the radioactive doses and thus the efficacy of the treatment
- the present invention relates to nanoprobes of formula I, defined above, characterized in that the group of formula (II) is complexed to a ligand or a radioelement to give a group of formula (III):
- a gamma radiation emitter radio-element or a positon emitter radio-element such "technetium, 64 copper, (67 ' 68) gallium, 124 iodine, or
- an alpha or beta negative radiation emitter radio-element such as 177 lutetium, yttrium, 166 holmium or 186 rhenium.
- the metallic ion is used for MRI or Manganese-enhanced magnetic resonance imaging (MEMRI) as a diagnostic tool.
- MRI Manganese-enhanced magnetic resonance imaging
- a gamma radiation emitter radio-element or a positon emitter radio-element is used in nuclear medicine, in particular gamma scintigraphy (GSc) and single photo emission computed tomography (SPECT) for gamma emitters, or positon emission tomography (TEP) for ⁇ + emitters as a diagnostic tool.
- GSc gamma scintigraphy
- SPECT single photo emission computed tomography
- TEP positon emission tomography
- An alpha or beta negative radiation emitter radio-element is used for curietherapy.
- Another advantage of the invention is the coupling of the recognition of specific cells by its poly ethylenegly col functionalized part, either with an imaging method for the localization and/or the diagnostic of pathology, or with a curing method such as curietherapy leading to the specific radiotherapy of cancer cells.
- the present invention relates to nanoprobes of formula I, having a group of formula (II) complexed to a ligand to give a group of formula (III), defined above, characterized in that their mean diameter is comprised from 2 to 60 nm, preferably from 15 to 50 nm, more preferably from 20 to 35 nm.
- nanoprobes present diffusion different from purely molecular edifice due to its small size.
- the nanoprobes Once administered by an intradermal route, the nanoprobes will be drained by a lymphatic way up to the first filter i.e. a node that the nanoprobes will be liable to cross due to its small size and then the nanoprobes will be drained in the lymphatic system up to thoracic channel
- the relaxivity that is an indicator of the efficacy as imaging agent of a compound, is equal or higher than the one of the prior art.
- the present invention relates to one of the nanoprobes defined above, characterized in that the formula (I) is chosen among the following formulae:
- Ri represents a group X such as defined above
- n is an integer comprised from 1 to 10
- r is an integer comprised from 1 to 20, r being > n
- R a represents a group chosen among:
- a biological molecule such as N,N-diallyl-L-DOPA, L-DOPA, an antibody, preferably a monoclonal antibody, in particular directed against antigens carried by tumor cells or tumor tissue, in particular anti-Cal5-3 or human Ipilimumab antibody, a peptide or any other vector such as an hormone in particular alpha melanocyte stimulating hormone (alpha-MSH), or heteroaromatic analog of iodo benzamide derivatives or quaternary ammoniums allowing the recognition of the nanoprobes by a cell, in particular a tumor cell, or
- biocompatible dye bearing at least one group -SO 3 R 3 wherein R 3 represents an hydrogen, sodium or calcium atom and eventually one or more groups chosen among -OH and -C0 2 H, or
- One of the advantages of the invention is to provide nanoprobes bearing in particular
- L-DOPA L-DOPA, liable to cross the blood brain barrier and to target specific receptors of the cancer cell, in particular neuroendocrine tumors or neuroblastomes.
- One of the advantages of the invention is to provide nanoprobes bearing in particular N,N-diallyl-L-DOPA, the diallyl groups of which are removed in vivo leading to nanoprobes bearing in particular L-DOPA.
- Antibody anti-Cal5-3 recognizes breast cancer cells.
- Human Ipilimumab antibody is an anti CTLA-4 receptor antibody from Bristol Myers Squibb for the treatment of melanoma.
- Quaternary ammoniums target proglycanes and allow detecting and treating cartilage tumors.
- the invention allows improving the diagnosis and staging of the tumor especially the node staging (by external detection with imaging of the tumor status of sentinel nodes) and proposes targeted therapy.
- the present invention relates to nanoprobes of formula (lal), (Ia2), (Ibl), (Ib2), (Icl), (Ic2) defined above, chosen among the following formulae:
- the present invention relates to nanoprobes chosen among (la la), (Ia2a), (lb la), or (Ib2a) comprising further a complexed "technetium.
- the present invention relates to nanoprobes of formula (I) wherein X represents a group of formula (II) complexed to a ligand to give a compound of formula (III), for its use as a medicament, suitable especially for detecting and/or treating a cancer cell or tissue or organ.
- the present invention relates to nanoprobes of formula (I) wherein X represents a group of formula (II) complexed to a ligand to give a compound of formula (III), for its use as a medicament, suitable especially for detecting and/or treating a cancer cell or tissue or organ, wherein said cancer is brain cancer.
- the present invention relates to nanoprobes of formula (I) wherein X represents a group of formula (II) complexed to a ligand to give a compound of formula (III),
- a cancer cell or tissue or organ for its use as a medicament, suitable especially for detecting and/or treating a cancer cell or tissue or organ, wherein said cancer is breast cancer and the organ is the sentinel node.
- Another advantage of the invention is to provide nanoprobes bearing in particular several biological effectors in particular antitumor antibodies, liable to recognize a node comprising tumor cells, and/or a fluorophore and/or a dye.
- the nanoprobes allow identifying by an external route by imaging metastatic nodes, in particular the sentinel node before surgery and during surgery.
- the knowledge before surgery of the tumor status of sentinel nodes allows adapting the surgical gesture to prevent a delayed second time of surgery or in contrast an usefulness node dissection.
- the liability to complex very simply a radio-element in the nanoparticles allows carrying out said complexation in a radio-pharmaceutical laboratory of a radio nuclear service.
- metabolic radiotherapy of hepatic tumors can be obtained by selective injection in the hepatic artery of nanoparticles complexed to toxic radio-elements (alpha or beta negative radiation emitter)
- the present invention relates to pharmaceutical or diagnostic compositions comprising nanoprobes of formula (I) wherein X represents a group of formula (II) complexed to a ligand to give a compound of formula (III).
- the pharmaceutical composition is liable to be administered i.v.
- the pharmaceutical composition is liable to be administered p. o. Doses can be easily determined by the one skilled in the art.
- Figures 1A to IE present the scintigraphic imaging (Single Photon Emission Computed Tomography SPECT) obtained with the nanoprobe (la la) after intraveinous injection in rats at a dose of 20 MBq of 99mTc-Dopadendron (Iala).
- Figure A 10 sec image at 1 min post-injection
- Figures D and E SPECT-CT images acquired at 30min to 1H30 after injection
- FIGS 1A to IE show a rapid vascular dispersion, a low liver uptake, a rapid and intense renal activity.
- Vascular activity persisted 20 minutes after IV injection.
- SPECT revealed a digestive uptake, such as observed in human after injection of 18F-Dopa.
- liver and vascular activity have disappeared, and only renal uptake was intense.
- RES reticuloendothelial system
- Figure 2 presents the 1H NMR (300 Mhz, CDC1 3 ) of allyl-protected compound 3.
- Figure 3 presents the 1H NMR (300 Mhz, CDCI3) of allyl-protected compound 4.
- Figure 4 presents the 1H NMR (300 Mhz, CDC1 3 ) of compound 6.
- Figure 5 presents the 13 C NMR (75 Mhz, CDC1 3 ) of compound 6.
- Figure 6 presents the 1H NMR (300 Mhz, CDC1 3 ) of compound 9.
- Figure 7 presents the 1H NMR (300 Mhz, CDC1 3 ) of compound 11.
- Figure 8 presents the 1H NMR (300 Mhz, CDC1 3 ) of compound 12.
- Figure 9 presents the 13 C NMR (75 Mhz, CDC1 3 ) of compound 12.
- Example 1.1 Catechol synthesis
- Reagents and solvents were purchased reagent grade and used without further purification.
- Example 1.2 N, N di-allyl-L-Dopa tris-catecholamide 17 and technetium complex thereof
- the compound 17 is dissolved in water (2 mL, 1 mg/mL).
- a solution (250 micro L) of stannous chloride (1 mg/mL, 1.3 mmol) in 0.1M hydrochloric acid is first added to the above solution and then the 99mTc(VII)04- solution (220 MBq mL/L).
- the resulting mixture is then stirred at room temperature for 15 min.
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